The Alcohol Research Center of The Scripps Research Institute (TSRI-ARC) proposes to continue its interdisciplinary program focused on the theme of the central nervous system effects of alcohol. For this renewal application, the TSRI-ARC will be a P60 consisting of 9 components plus an Educational Component. Four core components are proposed: Administrative, Animal Models/Biochemical Measures, Biochemical and Pilot. Five research components are proposed: Cellular Electrophysiology, Cellular Physiology, Neuroendocrinology, Neurochemistry, and Clinical Neurobehavioral. The overall hypothesis of the TSRI-ARC is that with chronic binge drinking, the brain reward systems become tolerant to alcohol while central stress systems become activated and that as a result, the neuroadaptive changes associated with chronic drinking produce an evolving set of neurobehavioral symptoms that include hypohedonia, anxiety, hyperarousal, sleep disturbances, and negative affect, conceptualized as the dark side of addiction. The subhypotheses for the present proposal are: (1) The transition from low levels of drinking (1-2 drinks within 2 hours in humans) to chronic binge drinking (4-5 drinks within 2 hours in humans) is driven by decreased activity of opioid peptide systems and endocannabinoid systems in reward circuits in the frontal cortex, and nucleus accumbens (Specific Aim 1). (2) The transition from binge drinking to dependence is driven by compromised function in the reward systems and recruitment of a dysregulated central stress system, most notably driven by changes in CRF, glutamate, and endocannabinoids in the extended amygdala (Specific Aim 2). (3) A particularly vulnerable local human clinical population has a phenotype of alcoholism that displays this transition from bingeing to dependence in young adulthood, allowing us to translate our findings in animals to humans and humans to animals (Specific Aim 3). We believe the proposed innovative approaches for testing these hypotheses will provide valuable insight into novel approaches for treating and preventing alcoholism in the human population. The TSRI-ARC also supports the Center at Large, which includes: 13 ROIs, 6 UOIs, one T32 NIAAA training grant, two R37s, one R13, one RC1 award. Members of the Center at Large have access to the Cores of the TSRI-ARC, the INIA Cores and the TSRI NIAAA Training Grant in Neuropsychopharmacology. Training and information dissemination to the San Diego community will be effected by the training opportunities of the Center including an NIAAA training grant and the Education Component.